1. Field of the Invention
The present invention relates to prostate specific membrane antigen (PSMA) binding compounds, chemical precursors of PSMA binding compounds and imaging methods of using the compounds.
2. Background
Prostate cancer (PCa) is the most commonly diagnosed malignancy and the second leading cause of cancer-related death in men in the United States (Cancer Facts & Figures; American Cancer Society: Atlanta, Ga., 2009). In 2009, it is estimated that 192,000 men will be diagnosed with prostate cancer and 27,000 men will die of the disease. Only one half of tumors due to PCa are clinically localized at diagnosis and one half of those represent extracapsular spread. Localization of that spread as well as determination of the total body burden of PCa have important implications for therapy, particularly as new combination and focal therapies become available.
The prostate-specific membrane antigen (PSMA), while expressed in prostate tumor epithelium, has a curious property in that it is expressed in the neovasculature of many solid tumors but not in that of prostate cancer (Chang et al., Cancer Res., vol. 59, pp. 3192-3198, 1999; Chang et al., Clin. Cancer Res., vol. 5, pp. 2674-2681, 1999; Gong et al., Cancer Metastasis Rev., vol. 18, pp. 483-490, 1999; Chang et al., Mol. Urol., vol. 3, pp. 313-320, 1999; Baccala et al., Urology, vol. 70, pp. 385-390, 2007; Chang et al., Urology, vol. 57, pp. 801-805, 2001 Milowsky et al., J. Clin. Oncol., vol. 25, pp. 540-547, 2007). Because of that property, an 111In-labeled monoclonal antibody to an extracellular epitope of PSMA, 111In-J591, was capable of identifying renal, bladder, lung, breast, colorectal and pancreatic tumors in a Phase I clinical imaging study (Milowsky et al., J. Clin. Oncol., vol. 25, pp. 540-547, 2007). That study validated 111In-J591 as a vascular targeting agent in human subjects. Since then other reports have further studied PSMA expression in certain tumor types. Baccala et al. noted that clear cell renal cell carcinoma expresses significantly more PSMA in its neovasculature than does the papillary variety (Baccala et al., Urology, vol. 70, pp. 385-390, 2007). Furthermore, angiomyolipoma, a benign renal lesion, did not express PSMA. As an enzyme with an extracellular active site, PSMA represents an excellent target for imaging and therapy directed toward solid tumor neovasculature in addition to prostate cancer itself. PSMA-based agents can report on the presence of this marker, which is increasingly recognized as an important prognostic determinate in PCa (Murphy et al., Urology, vol. 51, pp. 89-97, 1998). It is also the target for a variety of new PCa therapies (Galsky et al., J Clin Oncol, vol. 26, pp. 2147-2154, 2008).
ProstaScint™ is an 111In-labeled monoclonal antibody against PSMA that is clinically available for imaging PCa. Radioimmunotherapy based on ProstaScint™ and radiolabeled variations of this antibody are fraught with similar difficulties to the use of radiolabeled antibodies for imaging, including prolonged circulation times, poor target to nontarget tissue contrast, unpredictable biological effects and the occasional need for pre-targeting strategies, limiting the utility of these agents (Lange, P. H., Urology, vol. 57, pp. 402-406, 2001; Haseman et al., Cancer Biother Radiopharm, vol. 15, pp. 131-140, 2000; Rosenthal et al., Tech Urol, vol. 7, pp. 27-37, 2001). Furthermore, antibodies may have less access to tumor than low molecular weight agents, which can be manipulated pharmacologically.
The development of low molecular weight radiotherapeutic agents is much different from developing radiopharmaceuticals for imaging in that longer tumor residence times can often be important for the former.
Complete detection and eradication of primary tumor and metastatic foci are required to effect a cure in patients with cancer; however, current preoperative assessment often misses small metastatic deposits. More sensitive imaging techniques than computed tomography, magnetic resonance imaging and even positron emission tomography (PET), which can be used easily in the operating suite, are required. An old technique, recently revisited because of improved optics and fluorescent dye chemistry, is intraoperative photodiagnosis (PDD) (Toda, Keio J. Med., vol. 57, pp. 155-161, 2008). Fluorescein dyes have been used intraoperatively to identify brain tumors and verify the clarity of tumor margins since 1948 (Toda, Keio J. Med., vol. 57, pp. 155-161, 2008). A recent report describes its utility in identifying brain metastases (Okuda et al., Minim. Invasive Neurosurg., vol. 50, pp. 382-384, 2007). A long history of the use of 5-aminolevulinic acid (5-ALA) for brain tumor resection is also evident, and its use has been associated with improvement in progression-free survival (Stummer et al., Lancet Oncol., vol. 7, pp. 392-401, 2006). PDD can be performed easily during surgery due to the lack of a need for complex imaging equipment. All that is needed is a light-emitting diode to excite the fluorophore, which can be administered systemically or “painted” on the tissue directly. More recent incarnations of PDD have used quantum dots (Arndt-Jovin et al., IEEE Trans Nanobioscience, 2009), and more advanced dyes, such as indocyanine green (ICG) (Gotoh et al., J. Surg. Oncol., 2009), which emit in the near-infrared (NIR) region of the spectrum, enabling reasonable tissue penetration of emitted (and detected) light. Applications have included nontargeted approaches, such as preoperative evaluation of the vascular integrity of surgical flaps or identification of nodules of hepatocellular carcinoma (Matsui et al., Plast. Reconstr. Surg., vol. 123, pp. 125e-127e, 2009). Targeted approaches are also emerging, such as use of a fluorophore-conjugated anti-CEA antibody to identify colon or pancreatic cancer (Kaushal et al., J. Gastrointest. Surg., vol. 12, pp. 1938-1950, 2008), or the use of NIR activatable probes that emit light only when cleaved by a tumor-associated protease (Sheth et al., Gynecol. Oncol., vol. 112, pp. 616-622, 2009).
Recently, the application of 68Ga-labeled peptides has attracted considerable interest for cancer imaging because of the physical characteristics of Ga-68 (Reubi et al., J Nucl Med, vol. 49, pp. 1735-1738, 2008). Ga-68 is available from an in-house 68Ge/68Ga generator (68Ge, t1/2=270.8 day), which renders it independent of an onsite cyclotron. Therefore, 68Ga-based PET agents possess significant commercial potential and serve as a convenient alternative to cyclotron-based isotopes for positron emission tomography (PET), such as 18F or 124I. 68Ga has a high positron-emitting fraction (89% of its total decay). The maximum positron energy of 68Ga (max. energy=1.92 MeV, mean=0.89 MeV) is higher than that of 18F (max=0.63 MeV, mean=0.25 MeV). However, a study of spatial resolution using Monte Carlo analysis revealed that under the assumption of 3 mm spatial resolution for most PET detectors, the full-width-at-half-maximum (FWHM) of 18F and 68Ga are indistinguishable in soft tissue (3.01 mm vs. 3.09 mm) (Sanchez-Crespo et al., Eur J Nucl Med Mol Imaging, vol. 31, pp. 44-51, 2004). That finding implies that with the standard spatial resolution of 5 to 7 mm for current clinical scanners, image quality using 68Ga-based radiotracers will likely be indistinguishable from that of 18F-based agents, stimulating interest in the development of 68Ga-labeled compounds for medical imaging (Sanchez-Crespo et al., Eur J Nucl Med Mol Imaging, vol. 31, pp. 44-51, 2004; Khan et al., Eur J Surg Oncol, vol. 35, pp. 561-567, 2009; Fani et al., Contrast Media Mol Imaging, vol. 3, pp. 67-77, 2008). With a physical half-life of 68 min, 68Ga is also matched nicely to the pharmacokinetics of many peptides used for imaging. Few 68Ga-labeled, mechanism-based radiotracers for prostate cancer have been reported previously, and none for PSMA. Furthermore, 68Ga is introduced to biomolecules through macrocyclic chelators, which allows possible kit formulation and wide availability of the corresponding imaging agents.